Abstract

Abstract Targeting oncogenic signaling in the MAPK pathway can be achieved with small molecules such as trametinib, a MEK inhibitor (MEKi). Trametinib-induced MEK inhibition in KRAS-mutant (KRASmt) lung cancer, however, results in compensatory MAPK pathway re-activation through fibroblast growth factor receptor 1 (FGFR1). Combining MEK inhibition with FGFR1 inhibition should thereby combat this compensation; nonetheless, systemic administration of combination therapy faces its own set of challenges. Such challenges include delivering appropriate kinase inhibitor concentrations to target tumor tissue while avoiding dose-limiting additive toxicities. Although previous work has identified that combination therapy involving trametinib and FGFR inhibitor (FGFRi) ponatinib synergistically inhibits growth and proliferation of KRASmt cells, ponatinib interacts with a variety of targets and may mediate its synergistic effects via mechanisms not specific to FGFR1. To improve the efficacy at which we target KRASmt/FGFR-compensatory lung tumors, we encapsulated trametinib with a variety of FGFR1-specific inhibitors to form P-selectin-targeted nanoparticles. By formulating these nanoparticles, compensatory MAPK pathway activation through FGFR1 can be more efficaciously inhibited. Concurrently, greater concentrations of kinase inhibitor combinations can be locally delivered to lung tumors while mitigating toxic side effects that occur from systemic free drug. Here we show that these MEKi-FGFRi combination nanoparticles can be formulated to efficaciously inhibit growth and proliferation in KRASmt/FGFR-compensatory cancer cells. Citation Format: Arianna R. Izawa-Ishiguro, Ramya Sridharan, Christopher Wun, Tabassum J. Sami, Daniel A. Heller. MEKi-FGFRi combination nanoparticles for use against KRASmt/FGFR-compensatory lung tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 302.

Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call